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Hydroxamic Acid Analogue Histone Deacetylase Inhibitors Attenuate Estrogen Receptor- Levels and Transcriptional Activity: A Result of Hyperacetylation and Inhibition of Chaperone Function of Heat Shock Protein 90

Authors' Affiliations: ¹ Medical College of Georgia Cancer Center, Augusta, Georgia; ² H. Lee Moffitt Cancer Center, Tampa, Florida; ³ Yale University, New Haven, Connecticut; and ⁴ Novartis Pharmaceuticals, Inc., Cambridge, Massachusetts

Requests for reprints: Kapil Bhalla, MCG Cancer Center, Medical College of Georgia, 1120 15th Street, CN-2101 Augusta, GA 30912. Phone: 706-721-0566; Fax: 706-721-0469; E-mail: kbhalla{at}mcg.edu.

Purpose: The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)- in an active conformation, allowing it to bind 17ß-estradiol (E₂) and transactivate genes, including progesterone receptor (PR)-ß and the class IIB histone deacetylase HDAC6. By inhibiting HDAC6, the hydroxamic acid analogue pan-HDAC inhibitors (HA-HDI; e.g., LAQ824, LBH589, and vorinostat) induce hyperacetylation of the HDAC6 substrates -tubulin and hsp90. Hyperacetylation of hsp90 inhibits its chaperone function, thereby depleting hsp90 client proteins. Here, we determined the effect of HA-HDIs on the levels and activity of ER, as well as on the survival of ER-expressing, estrogen-responsive human breast cancer MCF-7 and BT-474 cells.

Experimental Design: Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ER, as well as apoptosis and loss of survival, were determined in MCF-7 and BT-474 cells.

Results: Treatment with HA-HDI induced hsp90 hyperacetylation, decreased its binding to ER, and increased polyubiquitylation and depletion of ER levels. HA-HDI treatment abrogated E₂-induced estrogen response element-luciferase expression and attenuated PRß and HDAC6 levels. Exposure to HA-HDI also depleted p-Akt, Akt, c-Raf, and phospho-extracellular signal–regulated kinase-1/2 levels, inhibited growth, and sensitized ER-positive breast cancer cells to tamoxifen.

Conclusions: These findings show that treatment with HA-HDI abrogates ER levels and activity and could sensitize ER-positive breast cancers to E₂ depletion or ER antagonists.

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